1. Field of the Invention
The invention relates generally to intracellular transports and transport complexes and, in particular, to polyfunctional molecules capable of delivering a desired pharmacological agent to a recipient. The invention also relates to methods for producing and using such molecules.
2. Background of the Technology
Many valuable compounds must be discarded as potential pharmaceuticals because of their pharmacokinetic profile. In some cases, the compound is cleared from circulation too rapidly, or accumulates to undesired levels in the kidneys or other organs, or is labile to digestive or circulatory enzymes or factors.
In light of the importance of surmounting the undesired pharmacokinetics of many compounds, a variety of drug delivery systems, such as liposomes, microspheres, antibodies, etc., all aimed at improving the therapeutic index and specificity of potential pharmaceuticals have been suggested (U.S. Pat. No. 6,245,358 (Adami, et al.).
For example, various efforts to encapsulate or entrap the desired pharmaceutical have been described (e.g., Yang, et al., “Controlled Release Tacrine Delivery System For The Treatment Of Alzheimer's Disease”, Drug Deliv., 8, 2, 93-98 (2001); Chandy, et al., “Development Of Poly (Lactic Acid)/Chitosan Co-Matrix Microspheres: Controlled Release Of Taxol-Heparin For Preventing Restenosis”, Drug Deliv., 8, 2, 77-86 (2001); Pignatello, et al., “Preparation And Analgesic Activity Of Eudragit RS100 Microparticles Containing Diflunisal”, Drug Deliv., 8, 1, 35-45 (2001). Likewise, liposome drug delivery formulations have been described (Singh, et al., “Receptor-Mediated Gene Delivery To Hepg2 Cells By Ternary Assemblies Containing Cationic Liposomes And Cationized Asialoorosomucoid”, Drug Deliv., 8, 1, 29-34 (2001); Petrikovics, et al., “In Vitro Studies On Sterically Stabilized Liposomes (SL) As Enzyme Carriers In Organophosphorus (OP) Antagonism”, Drug Deliv., 7, 2, 83-89 (2001). Such approaches to drug delivery are reviewed by Gupta, et al. (“Biodegradable Polymer Microspheres As Vaccine Adjuvants And Delivery Systems”, Dev Biol Stand, 92, 63-78 (1998).
Additionally, active agents have been coupled or conjugated to polymeric compounds in an attempt to improve the delivery of the active agent. For example, camptothecin has been conjugated to poly(L-glutamic acid) (PG) (Zou, et al., “Effectiveness Of Water Soluble Poly(L-Glutamic Acid)-Camptothecin Conjugate Against Resistant Human Lung Cancer Xenografted In Nude Mice”, Int J Oncol., 18, 2, 331-336 (2001). The anticancer agent, paclitaxel, has likewise been conjugated to poly(L-glutamic acid) and found to possess improved pharmacokinetic properties (Oldham, et al., “Comparison Of Action Of Paclitaxel And Poly(L-Glutamic Acid)-Paclitaxel Conjugate In Human Breast Cancer Cells”, Int J Oncol., 16, 1, 125-32 (2000). Similarly, Pechar, et al. describe the synthesis of a water-soluble polymer drug carrier system based on biodegradable poly(ethylene glycol) block copolymer, and its use to produce a conjugate of doxorubicin. The copolymer consisted of PEG blocks of molecular weight 2000 linked by means of an oligopeptide having amino end groups. Each of the oligopeptide blocks incorporated in the carrier contained three carboxylic groups of which some were used for attachment of the doxorubicin via an enzymatically cleavable tetrapeptide spacer Gly-Phe-Leu-Gly (Pechar, et al., “Poly(Ethylene Glycol) Multiblock Copolymer As A Carrier Of Anti-Cancer Drug Doxorubicin”, Bioconjug Chem., 11, 2, 131-139 (2000). Drug polymer conjugates containing acid-cleavable bonds are reviewed by Kratz, et al., “Drug Polymer Conjugates Containing Acid-Cleavable Bonds”, Crit Rev Ther Drug Carrier Syst., 16, 3, 245-88 (1999). Such approaches to drug delivery are reviewed by Sezaki, et al. (“Macromolecule-Drug Conjugates In Targeted Cancer Chemotherapy”, Crit Rev Ther Drug Carrier Syst., 1, 1, 1-38 (1984).
Drug delivery systems comprising dendrimers and dendrimer conjugates are also known. See, for example, U.S. Pat. Nos. 4,289,872; 4,360,646; 4,410,688, 4,587,329; 5,229,490; 5,338,532; 5,527,524; 5,714,166; 5,882,645; and 6,194,543.
Despite such efforts, a need continues for a delivery vehicle that can improve the pharmacokinetics of pharmacological agents. The present invention is directed to such a need.